Abstract Inflammatory breast cancer (IBC) is the most lethal form of breast cancer with median survival of about 4 years compared with more than 10 years for other forms of breast cancer. Poor prognosis is associated with the high propensity of these tumors to develop distant metastases. Despite a higher incidence of certain molecular alterations in IBC, genetic profiling studies have failed to identify a specific therapeutic target and there are currently no FDA-approved targeted therapies that are unique for the disease. The majority of IBC tumors lack estrogen receptor ? (ER?) suggesting the potential of ER? to mediate effects of estrogen in these tumors. Unlike the oncogenic ER?, ER? is associated with epithelial differentiation and decreased invasion in non-IBC. To investigate whether ER? has a similar role in IBC, we analyzed human tumor tissues and datasets. Our findings are the first to indicate expression of ER? in more than 50% of IBCs and correlation of the receptor with better survival. To investigate whether this association reflects the ability of ER? to inhibit metastasis, we studied preclinical models of IBC. Knockout of ER? in IBC cells promotes through cytoskeleton remodeling migration and activates molecules such as RhoC that are associated with cell motility and metastasis in IBC. Conversely, ligands that activate ER? potentiate its anti-migratory activity. Consistent with the in vitro anti- migratory activity, ER? proficient cells are less metastatic than ER? knockout cells during preliminary analysis of orthotopic and lung colonization models of IBC. We, therefore, hypothesize that ER? and its agonists prevent progression and metastasis of IBC tumors. Our proposed research will: 1) determine the role of ER? and its agonists in progression and metastasis of IBC, 2) elucidate the mechanism of the anti-metastatic activity of ER? and 3) examine whether ER? is inversely associated with metastasis in IBC. To investigate the role of ER? in metastasis of IBC, we will examine how the receptor alters the metastatic potential of IBC cells and tumors in vitro and in vivo. We will also evaluate the efficacy of ER? ligands, that are currently in clinical trials, to inhibit metastasis of IBC xenografts ensuring that our studies will impact the clinical treatment of IBC (Aim 1). Further, we will delineate the molecular mechanisms of ER? action by analyzing specific pathways that are implicated in disease progression and metastasis (Aim 2). Finally, we will analyze clinical samples to validate the expression of ER? in tumors and verify its inverse association with metastasis (Aim 3). By defining the role of ER? and its associated pathways in progression and metastasis of IBC our research will provide insights into the biology of IBC and assist to better understand why these tumors become metastatic. Our study will also have important clinical implications by establishing ER? as a novel and specific therapeutic target that benefits patients with IBC. Our findings can directly be translated into advances in clinical setting because they will validate a new therapeutic compound, the ER? ligands, that either alone or in combination with other drugs can substantially repress IBC metastasis and eliminate its associated mortality.